Hepatocellular carcinoma (HCC) is an aggressive malignancy that is often refractory to chemotherapy and immune checkpoint inhibitors. This therapeutic resistance is driven in part by the persistence of cancer stem-like cells (CSCs) and the development of an immune-cold tumor microenvironment. However, the upstream regulators that coordinate these malignant features remain poorly defined. In this study, we identified dysadherin as a novel upstream activator of YAP that promotes both CSC plasticity and immune evasion through the FAK/YAP/TEAD2 signaling axis. Using single-cell transcriptomic analysis, in vitro assays, and multiple in vivo models including a humanized immune mouse system, we showed that dysadherin enhances the expression of pluripotency genes, such as OCT4 and upregulates PD-L1. These changes support stem-like tumor behavior and contribute to T-cell exclusion, fostering an immunosuppressive niche. Notably, genetic knockdown or peptide-based pharmacologic inhibition of dysadherin effectively restored antitumor immune activation, suppressed metastasis and improved therapeutic responsiveness. Our findings reveal a mechanistic link between dysadherin-mediated cell adhesion signaling and the transcriptional regulation of both stemness and immune escape. Collectively, these findings establish the dysadherin/YAP axis as a key driver of HCC progression and resistance, and highlight it as a compelling therapeutic target that could overcome treatment failure in advanced liver cancer.